Poor water-solubility is known to be a limiting factor bioavailability. Many attempts have been done with the aim to improving the bioavailability of water-insoluble and water-sparingly soluble drugs. Most such formulations were immediate release in nature as this generally maximizes the amount of drug absorbed. Micronization, solid dispersion and micelle-formation are common techniques used to enhance the drug solubility.
Solid dispersion has been prepared by solvent evaporation, by spray drying, by spraying drug solution onto a carrier, by twin screw extrusion, by melt fusion, by mechanical admixture such as by ball milling and by mechanical admixture at an elevated but non-melting temperature, as described in U.S. Pat. No. 6,706,283.
Solid dispersion has been suggested by several U.S. patents. U.S. Pat. No. 5,281,420 teaches compositions in dosage form comprising a solid dispersion which is a solidified melt mixture consisting of tebufelone, a poloxamer surfactant and other components. The other components are miscible with a melt mixture of components. U.S. Pat. No. 7,273,624 has taught a composition of an active ingredient embedded amorphously in particular. The author emphasizes that there are essentially no crystalline contents of any constituent in their particular embodiment. U.S. Pat. No. 4,654,296 teaches a solid dispersion composition containing dihydropyridien A uniformly dispersed in hydroxypropylmethyl cellulose. U.S. Pat. No. 5,028,433 teaches a readily absorbable drug formulation by incorporating to a water-soluble or enteric polymer. U.S. Pat. No. 5,514,663 teaches a composition comprising 3-15 mg of sennosides, wherein the sennosides are in a solid dispersion. U.S. Pat. No. 5,631,022 teaches a composition wherein the drug is in a solid dispersion in a water-soluble carrier. U.S. Pat. No. 5,651,983, U.S. Pat. No. 5,843,479 and U.S. Pat. No. 5,656,290 teach a solid dispersion of bisacodyl on a hydrophilic substrate. U.S. Pat. No. 6,174,873 suggests a solid dispersion comprising a carrier selected from the group consisting of polyethylene glycol, polyvinylpyrrolldone, hydroxypropylmethyl cellulose, phosphatidylcholine, polyoxyethylone hydrogenated castor oil, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose, ethyl cellulose and stearic acid.
Application of solid dispersion on oral extended release tablet for treating diseases has been described in U.S. Pat. No. 6,706,283 and other articles. U.S. Pat. No. 5,162,117 teaches a controlled release tablet of flutamide. The core comprises 20-80 percent of flutamide and a carrier capable of forming a solid dispersion with flutamide. U.S. Pat. No. 5,773,025 teaches a bioavailable sustained release oral solid dosage form comprising agglomerated particles of a therapeutically active medicament in amorphous form.
Several articles teach tablet composition comprising nano- or submicron particles. U.S. Pat. No. 5,932,245 suggests a dosage formulation that provides for the release of nanoparticles, wherein the nanoparticles have inner phase and outer phase. Both phases are charged. U.S. Pat. No. 5,972,389 teaches a controlled release oral drug dosage form for releasing a vesicle-containing drug into the stomach, duodenum, and intestinal areas which contain Peyer's patches of a patient, wherein said drug is soluble, but is rendered sparingly soluble when contained in said vesicle, and wherein the vesicle is a member selected from the group consisting of a liposome, nanoparticle, nanosphere and nanocapsule. U.S. Pat. No. 7,803,748 teaches a composition of nanoparticles wherein the nanoparticles enhance paracellular transport of at least one bioactive agent and wherein said nanoparticles are further configured in a tablet form with one or more excipients.
It is known that unstable solid dispersion converts to a crystal form over the time, while nano-particle aggregation or even fusion may happen during the process or storage. Thus, there remains a need for a novel pharmaceutical dosage structure and/or composition comprising an amorphous structure and submicron particle allowing more flexibility for formulation development. A flexible formulation comprising an amorphous structure and submicron particle may allow a reduction of instability during storage or even improved bioavailability compared to conventional tablet dosage forms.